L-carnitine salt and cosmetic and pharmaceutical compositions containing same for treating dermatoses

ABSTRACT

L-carnitine trichloroacetate and its use for producing cosmetic and pharmaceutical compositions suitable to be topically applied for the treatment of dermatoses, are disclosed.

The present invention relates to a novel L-carnitine salt and the usethereof for producing cosmetic and pharmaceutical compositions whichcontain such salt, suitable to be topically applied for the treatment ofdermatoses.

This novel L-carnitine salt is L-carnitine trichloroacetate of formula(I) ##STR1## L-carnitine trichloroacetate is a highly stable andnon-hygroscopic salt. This is quite surprising since trichloroaceticacid is an extremely deliquescent compound. Surprising as well is theactivity of this novel salt in the dermatologic field sincetrichloroacetic acid exhibits a caustic and revulsive vesicant action.

In the following example the preparation of L-carnitine trichloroacetateis described.

EXAMPLE

Preparation of L-carnitine trichloroacetate (ST 1162) L-carnitine innersalt (16.1 g; 0.1 moles) was dissolved in 100 mL H₂ O. To the resultingsolution, trichloroacetic acid (16.4 g; 0.1 moles) dissolved in 100 mLH₂ O, was added.

The resulting solution was concentrated under vacuum at 40°. The solidresidue which formed was taken up with acetone and the solid filteredoff. 31 g of the title compound were obtained. The compound wascrystallized from hot isopropanol. Melting Point 79,3° C. (DSC).

The compound was stable and non-hygroscopic.

    ______________________________________                                        Elementary analysis: C.sub.9 H.sub.16 NO.sub.5 Cl.sub.3                                  C %  H %        N %    Cl %                                        ______________________________________                                        calculated   33.30  4.96       4.31 32.77                                     found        33.32  5.09       4.36 32.69                                     ______________________________________                                    

H₂ O content 1.1%

pH=2.8, H₂ O [α]_(D) ²⁵ =15,1° (c=1%, H₂ O )

HPLC column: (L-carnitine) μ Bondapak-NH₂ (10 μm) 300 mm×3,9 mmTemperature: 30° C. mobilephase: CH₃ CN/KH₂ PO₄ 50 mM pH 5,2 65/35Flow-rate: 1,0 ml/min L-carnitine: R_(t) =8,21 min 51,9% Column:(trichloroacetic acid) IONPAC-AS4A/SC Eluant: NaOH 50 mM Flow-rate: 1,0ml/min room temperature Trichloroacetic acid Rt=6,06 min 48,4%

NMR D₂ O δ4.5-4.4 (LH,m, CHOH); 3.3 (2H, m, CH₂ N+); 3.1 (9 h, s,(CH₃)₃N+); 2.5(2H,dd,CH₂ COO)

L-carnitine trichloroacetate is used as active ingredient for producingcosmetic and dermatologic pharmaceutical compositions suitable to betopically applied.

The dermatoses which are suitably treated with the compositions of thepresent invention are in particular ichthyosis, psoriasis and thosedermatoses which are induced by a defective keratinization, such asdandruff, acne and palmar and plantar hyperkeratosis.

Ichthyosis is a dermatosis characterized by generalized dryness,harshness and scaling of the skin. It may occur as a hereditary diseasepresent at birth, or as a metabolic disorder associated withhypothyroidism or with the intake of drugs (such as butyrophenols)inhibiting lipid synthesis, or as a paraneoplastic syndrome,manifestation of a tumor process involving internal organs.

Xeroderma, the mildest form of ichthyosis is neither congenital norassociated with systemic abnormalities. It usually occurs on the lowerlegs of middle-aged or older patients, most often in cold weather and inpatients who bathe frequently. There may be mild to moderate itching andan associated dermatitis due to detergents or other irritants.

The inherited ichthyoses, all characterized by excessive accumulation ofscale on the skin surface, are classified according to clinical,genetic, and histologic criteria.

Known treatments of any form of ichthyosis comprise topically applyingto the skin hydrating emollients. Furthermore, salicylic acid or vitaminA-containing ointments have been widely used.

A keratolytic agent particularly effective in removing the scale inichthyosis vulgaris, lamellar ichthyosis and sex-linked ichthyosiscontains 6% salicylic acid in a gel composed of propylene glicol, ethylalcohol, hydroxypropylene cellulose and water.

Further known drugs for the the treatment of this disorder include: 50%propylene glicol in water, hydrophilic petrolatum and water (in equalparts), and cold cream and an a-hydroxy acid (e. g. lactic and pyruvicacid) in various bases. In lamellar ichthyosis, 0.1% tretinoin (vitaminA acid; retinoic acid) cream has been utilizad. None of these treatmentshas been found satisfactorily effective.

Hyperkeratosis is a thickening of the stratum corneum of the skin.

The treatment of choice is the topical application of drugs containingurea, propylene glicol or salicylic acid. Also in this case, none of theknown treatment has proved to be satisfactorily effective.

It has now been found that the compound of the present invention, whentopically applied as solutions, lotions, creams of ointments containingfrom 0,01% to 20%, preferably from 1% to 15% and most preferably from 2to 10% by weight of at least one of the foregoing compounds, arepotently effective in achieving complete remission of ichthyoticconditions in humans and in healing psoriasis and those disordersbrought about by an altered keratinization, such as danddruff, acne andpalmer and plantar hyperkeratosis. It has also been found that, if thesolutions, creams or ointments of the invention are applied regularly ona daily basis, within about two to three weeks the effected skin areaswill return to normal conditions.

In order to prepare the compositions of this invention, L-carnitinetrichloroacetate is preferably dissolved in water or ethanol initially.The solution thus prepared may be admixed in the conventional mannerwith commonly available ointment bases such as hydrophilic ointment(USP) or petrolatum (USP).

The water or ethanol used to dissolve the compounds according to thisinvention may range in concentration of from 1 to 30%, by volume, of thetotal composition. The compounds of this invention may also beformulated in a solution or lotion form.

For istance, an ester according to the invention is dissolved directlyin a mixture of water, ethanol and propylene glicol (40:40:20 byweight).

Some examples of the formulation are herein below described:

Formulation 1:5% solution

5 grams of the salt were dissolved in 5 mL of water and the resultingsolution admixed with 40 mL of ethanol and 20 mL of propylene glicol.Sufficient water was added to make 100 mL of formulation.

Formulation 2:5% ointment

5 grams of the salt were admixed with 95 grams of USP grade hydrophilicointment, until an uniform consistence resulted.

We claim:
 1. L-carnitine trichloroacetate of formula (I) ##STR2##
 2. Apharmaceutical composition, which comprises(A) the compound of formula(I): ##STR3## and (B) a pharmacologically acceptable carrier.
 3. Thecomposition of claim 2, for treating ichthyosis and psoriasis.
 4. Thecomposition of claim 2 for treating dermatoses brought about bydefective keratinization.
 5. The composition of claim 4, for treatingdandruff, acne and palmar and plantar hyperkeratosis.
 6. The compositionof claim 2, which is in the form of a solution, lotion, ointment, orcream.
 7. The composition of claim 6, which comprises from 0.1% to 20%by weight of said compound of formula (I).
 8. The composition of claim6, which comprises from 1% to 15% by weight of said compound of formula(I).
 9. The composition of claim 6, which comprises from 2% to 10% byweight of said compound of formula (I).
 10. A method for treatingdermatosis, which comprises topically administering an effective amountof the compound of formula (I): ##STR4## to a patient in need thereof.11. The method of claim 10, wherein said dermatosis is selected from thegroup consisting of ichthyosis and psoriasis.
 12. The method of claim10, wherein said dermatoses is brought about by defectivekeratinization.
 13. The method of claim 12, wherein said dermatosis isselected from the group consisting of dandruff, acne and palmar andplantar hyperkeratosis.
 14. The method of claim 10, wherein saidcompound of formula (I) is applied in a composition in the form of asolution, lotion, ointment or cream.
 15. The method of claim 14, whereinsaid composition comprises from 0.1% to 20% by weight of said compoundformula (I).
 16. The method of claim 14, wherein said compositioncomprises 1% to 15% by weight of said compound of formula (I).
 17. Themethod of claim 14, wherein said composition comprises 2% to 10% byweight of said compound of formula (I).